Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:33])[CH2:7][CH2:6][CH:5]([N:8]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([O:31]C)=[O:30])[CH:24]=3)=[CH:19][CH:18]=2)[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:4][CH2:3]1.O[Li].O.O>C1COCC1>[CH3:1][C:2]1([CH3:33])[CH2:3][CH2:4][CH:5]([N:8]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([OH:31])=[O:30])[CH:24]=3)=[CH:19][CH:18]=2)[C:9]([O:11][C:12]([CH3:13])([CH3:14])[CH3:15])=[O:10])[CH2:6][CH2:7]1
Reactant: COC(=O)c1cccc(-c2ccc(CN(C(=O)OC(C)(C)C)C3CCC(C)(C)CC3)cc2)c1
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Product: CC1(C)CCC(N(Cc2ccc(-c3cccc(C(=O)O)c3)cc2)C(=O)OC(C)(C)C)CC1

Procedure:
A mixture of methyl 4′-[((4,4-dimethylcyclohexyl){[(1,1-dimethylethyl)oxy]carbonyl}-amino)methyl]-3-biphenylcarboxylate (0.850 g; 1.88 mmol), LiOH.H2O (0.395 g; 9.40 mmol), water (2 mL) and THF (20 mL) was heated under reflux for 24 h, cooled and concentrated in vacuo. The residue was partitioned between EtOAc/1N KHSO4, layers were separated and the organic layer was extracted with EtOAc (×2). combined organics were washed (water, brine), dried over Na2SO4 and concentrated in vacuo affording the title compound as a colorless foam. LC/MS (method E) tR 0.77 min; m/z 464 (M−H).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[NH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1.CC(O)=O>ClCCCl>[F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][N:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)=[CH:4][CH:3]=1
Reactant: C1CCNCC1
Reactant: O=Cc1ccc(F)cc1
Solvent: ClCCCl
Solvent: CC(=O)O
Product: Fc1ccc(CN2CCCCC2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 93.4 %

Procedure:
To a stirred solution of 4-fluorobenzaldehyde (500 mg, 4.0 mmol) in DCE (3 ml) at RT was added piperidine (309 mg, 3.6 mmol) followed by AcOH (242 mg, 4.0 mmol). The solution was stirred at RT for 2 h, and then STAB (1.3 g, 6.05 mmol) was added in one portion. The resulting mixture was stirred at RT overnight and then quenched with saturated NaHCO3 (10 ml). The organic layer was separated, dried (Na2SO4), filtered and concentrated at reduced pressure. Purification by silica flash column chromatography (eluting with DCM/MeOH/NH3 90:10:1) provided the title compound as colourless oil (650 mg, 95%).
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([O:8][CH3:9])=[CH:6][CH:7]=1.[C:10]1(OB(O)O)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C1(C)C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O1CCCC1.CO>[C:10]1([C:2]2[N:3]=[N:4][C:5]([O:8][CH3:9])=[CH:6][CH:7]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: OB(O)Oc1ccccc1
Reactant: COc1ccc(Cl)nn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc(-c2ccccc2)nn1
Temperature: 85 °C
Yield: 46.6 %

Procedure:
A mixture of 3.0 g of 3-chloro-6-methoxypyridazine, 3.8 g of phenylboric acid, 2.4 g of tetrakis(triphenylphosphine)palladium(0), 160 ml of toluene, 40 ml of methanol, 80 ml of an aqueous 2 mol sodium carbonate solution and 30 ml of tetrahydrofuran was stirred under heating at 85° C. for one hour. After cooling as it was, the reaction solution was extracted with ethyl acetate. The organic phase was washed with brine and eluted with ethyl acetate through NH-silica gel (Fuji Silicia). After removing the solvent, the residue was crystallized, to give 1.8 g of the target compound.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[NH:5][C:4](=[O:9])[C:3]=1[C:10]([O:12][CH2:13][CH3:14])=[O:11].[F:15][C:16]1[CH:21]=[CH:20][C:19](B(O)O)=[CH:18][CH:17]=1.N1C=CC=CC=1>O1CCOCC1>[F:15][C:16]1[CH:21]=[CH:20][C:19]([N:5]2[C:6]([CH3:8])=[CH:7][C:2]([CH3:1])=[C:3]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:4]2=[O:9])=[CH:18][CH:17]=1
Reactant: OB(O)c1ccc(F)cc1
Reactant: CCOC(=O)c1c(C)cc(C)[nH]c1=O
Solvent: C1COCCO1
Solvent: c1ccncc1
Product: CCOC(=O)c1c(C)cc(C)n(-c2ccc(F)cc2)c1=O
Temperature: 80 °C
Yield: 16.6 %

Procedure:
A suspension of ethyl 4,6-dimethyl-2-oxo-1,2-dihydropyridine-3-carboxylate (5.0 g, 0.025 mol), 4-fluorophenylboronic acid (10.7 g, 0.077 mol), cupric acetate (1.33 g, 0.007 mol), pyridine (6.86 mL), and 4 A molecular sieves (5.0 g) in 1,4-dioxane (80 mL) is heated at 80° C. for 68 hours. The solids are filtered off and the filtrate is concentrated. The residue is partitioned with EtOAc (50 mL) and 2N HCl (70 mL). The precipitated solid is collected by filtration and washed with EtOAc to give the title product (1.2 g). The EtOAc filtrate is separated, dried and concentrated. The residue is purified by silica gel column chromatography eluting with PE:EtOAc:MeOH (40:20:1) to give another portion of product (0.12 g), (1.32 g total, 17.8% yield). MS (m/z): 290.1 (M+H).
Reaction SMILES: [H-].[Na+].[I-].[CH3:4][S+](C)(C)=O.[CH2:9]([O:16][C:17]1[CH:24]=[CH:23][C:20]([CH:21]=[O:22])=[CH:19][CH:18]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>CS(C)=O.C1COCC1>[CH2:9]([O:16][C:17]1[CH:18]=[CH:19][C:20]([CH:21]2[CH2:4][O:22]2)=[CH:23][CH:24]=1)[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: O=Cc1ccc(OCc2ccccc2)cc1
Reactant: C[S+](C)(C)=O
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: C1CCOC1
Product: c1ccc(COc2ccc(C3CO3)cc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
NaH (60%, 0.5 g, 23.6 mmol) was diluted in DMSO (50 mL) and stirred for 30 min at rt under nitrogen. Trimethylsulfoxonium iodide (7.8 g, 35.37 mmol) was added in portions at 0° C. The reaction mixture was stirred for 1 h. Then a solution of 4-benzyloxybenzaldehyde (5 g, 23.58 mmol) in THF (15 mL) was added. The reaction solution was stirred at rt for 3 h. The reaction mixture was poured into ice-water and extracted with ether. The organic layer was dried over Na2SO4 and concentrated to give 2-(4-(benzyloxy)phenyl)oxirane, which was used for the next step without further purification.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:12]3[N:13]=[C:14]4[C:20]([C:21]([OH:23])=O)=[CH:19][NH:18][C:15]4=[N:16][CH:17]=3)=[N:7][N:8]2[CH3:11])=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.CCN=C=NCCCN(C)C.[NH2:44][C:45]([CH3:57])([CH3:56])[CH2:46][CH2:47][NH:48][C:49](=[O:55])[O:50][C:51]([CH3:54])([CH3:53])[CH3:52]>CN(C=O)C.CN(C1C=CN=CC=1)C.O>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:12]3[N:13]=[C:14]4[C:20]([C:21]([NH:44][C:45]([CH3:57])([CH3:56])[CH2:46][CH2:47][NH:48][C:49](=[O:55])[O:50][C:51]([CH3:53])([CH3:52])[CH3:54])=[O:23])=[CH:19][NH:18][C:15]4=[N:16][CH:17]=3)=[N:7][N:8]2[CH3:11])=[CH:4][CH:3]=1
Reactant: Cn1nc(-c2cnc3[nH]cc(C(=O)O)c3n2)c2ccc(F)cc21
Reactant: CC(C)(N)CCNC(=O)OC(C)(C)C
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: Cn1nc(-c2cnc3[nH]cc(C(=O)NC(C)(C)CCNC(=O)OC(C)(C)C)c3n2)c2ccc(F)cc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 69.4 %

Procedure:
To a stirred solution of 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (100 mg, 0.32 mmol) and DIEA (124 mg, 0.96 mmol) in 6 mL of DMF was added EDCI (123 mg, 0.64 mmol) and DMAP (110 mg, 0.90 mmol) at room temperature followed by tert-butyl 3-amino-3-methylbutylcarbamate (260 mg, 1.28 mmol) in one portion and the mixture was stirred at room temperature for 16 hours. The reaction mixture was poured into 40 mL of water, filtered and the filter cake was washed with petroleum ether to give tert-butyl 3-(2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamido)-3-methylbutylcarbamate (110 mg, 69.4%) as a yellow solid which was used for the next step without further purification. MS: (M+H)+=496.2.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[S:15][C:16]1[CH:17]=[C:18]([CH:20]=[CH:21][CH:22]=1)[NH2:19].[CH:23]([C:26]1[O:30][N:29]=[C:28]([NH:31][C:32](=O)[O:33]C2C=CC=CC=2)[CH:27]=1)([CH3:25])[CH3:24]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[S:15][C:16]1[CH:17]=[C:18]([NH:19][C:32]([NH:31][C:28]2[CH:27]=[C:26]([CH:23]([CH3:25])[CH3:24])[O:30][N:29]=2)=[O:33])[CH:20]=[CH:21][CH:22]=1
Reactant: COc1cc2ncnc(Sc3cccc(N)c3)c2cc1OC
Reactant: CC(C)c1cc(NC(=O)Oc2ccccc2)no1
Product: COc1cc2ncnc(Sc3cccc(NC(=O)Nc4cc(C(C)C)on4)c3)c2cc1OC
Yield: 69 %

Procedure:
The title compound was prepared using the procedure described in Example 113C with 3-(6,7-dimethoxyquinazolin-4-ylthio)aniline described in Example 115B (94 mg, 0.3 mmol) and phenyl 5-isopropylisoxazol-3-ylcarbamate described in Example 133A (110 mg, 0.45 mmol). Precipitation of the desired product detected completion of reaction. The solid was filtered off and washed with diethyl ether to give 1-(3-(6,7-dimethoxyquinazolin-4-ylthio)phenyl)-3-(5-isopropyl isoxazol-3-yl)urea (96.26 mg, 69%) as a solid. 1H NMR (300 MHz, DMSO-d6) δ 9.57 (s, 1H), 9.02 (s, 1H), 8.70 (s, 1H), 7.84 (s, 1H), 7.53-7.42 (m, 2H), 7.36-7.27 (m, 3H), 6.51 (s, 1H), 3.99 (s, 6H), 3.04-3.00 (m, 1H), 1.23 (d, 6H); LC-MS (ESI) m/z 466 (M+H)+.
Reaction SMILES: [C:1]([C:3]1[CH:12]=[CH:11][C:6]([C:7]([NH:9][NH2:10])=O)=[CH:5][CH:4]=1)#[N:2].[CH3:13]OC(OC)N(C)C.[NH2:21][C:22]1[C:23](=[O:43])[N:24]([CH2:40][CH2:41][CH3:42])[C:25](=[O:39])[N:26]([C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([C:35]([F:38])([F:37])[F:36])[CH:30]=2)[C:27]=1[CH3:28].C(O)(=O)C>CN(C)C=O.O>[CH3:28][C:27]1[N:26]([C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([C:35]([F:37])([F:36])[F:38])[CH:30]=2)[C:25](=[O:39])[N:24]([CH2:40][CH2:41][CH3:42])[C:23](=[O:43])[C:22]=1[N:21]1[CH:13]=[N:10][N:9]=[C:7]1[C:6]1[CH:11]=[CH:12][C:3]([C:1]#[N:2])=[CH:4][CH:5]=1
Reactant: CCCn1c(=O)c(N)c(C)n(-c2cccc(C(F)(F)F)c2)c1=O
Reactant: COC(OC)N(C)C
Reactant: N#Cc1ccc(C(=O)NN)cc1
Solvent: CN(C)C=O
Solvent: O
Solvent: CC(=O)O
Product: CCCn1c(=O)c(-n2cnnc2-c2ccc(C#N)cc2)c(C)n(-c2cccc(C(F)(F)F)c2)c1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 4-cyanobenzohydrazide (46.0 mg) and dimethylformamide dimethylacetal (110 μl) in N,N-dimethy formamide (2.0 ml) was stirred at 50° C. for thirty minutes and then cooled to room temperature, and thereto were added 5-amino-6-methyl-3-propyl-1-(3-trifluoromethylphenyl)pyrimidin-2,4(1H,3H)-dione (prepared in Reference Example 193) (20.0 mg) and acetic acid (0.5 ml) and the resulting mixture was stirred at 130° C. for eight hours. To the reaction mixture was added water (10 ml) and the resulting mixture was extracted with ethyl acetate (10 ml×2). The organic layer was washed with water (10 ml×2) and saturated saline (20 ml), dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: chloroform/methanol) to afford 4-[4-[6-methyl-2,4-dioxo-3-propyl-1-(3-trifluoromethylphenyl)-1,2,3,4-tetrahydropyrimidin-5-yl]-4H-1,2,4-triazol-3-yl]benzonitrile (7.8 mg).
Reaction SMILES: [OH:1][CH:2]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH2:3][CH2:4][NH2:5].CC1(C)CCCC(C)(C)N1.[F:22][C:23]1[CH:30]=[CH:29][CH:28]=[CH:27][C:24]=1[CH2:25]Cl>C(#N)C>[F:22][C:23]1[CH:30]=[CH:29][CH:28]=[CH:27][C:24]=1[CH2:25][NH:5][CH2:4][CH2:3][CH:2]([OH:1])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: Fc1ccccc1CCl
Reactant: NCCC(O)c1ccccc1
Agent: CC1(C)CCCC(C)(C)N1
Solvent: CC#N
Product: OC(CCNCc1ccccc1F)c1ccccc1
Yield: 52.5 %

Procedure:
A mixture of 3-hydroxy-3-phenylpropylamine (7.0 g, 46 mM) and 2,2,6,6-tetramethylpiperidine (7.9 ml, 46 mM) in acetonitrile (100 ml) was treated with a solution of o-fluorobenzyl chloride (6.75 g, 46 mM) in acetonitrile (10 ml). After 24 hours the resulting precipitate was removed by filtration and washed with acetonitrile (2×10 ml). The combined filtrate and washings were evaporated under reduced pressure and the residue partitioned between 2 N hydrochloric acid (50 ml) and ether (100 ml). The aqueous layer was basified by extracted with ether, the ether extracts dried and evaporated. Chromatography on Grade 3 silica using 2% methanol in chloroform as eluant followed by distillation gave the title compound (6.3 g) b.p. 156°-160° C. (0.2 mbar). Found: C, 73.9; H, 7.1; N, 5.2%; C16H18FNO requires: C, 74.1; H, 7.0; N, 5.4%.
Reaction SMILES: C([C:4]1[CH:9]=[CH:8][C:7]([C:10](=[O:12])[CH3:11])=[CH:6][CH:5]=1)(=O)C.[NH2:13][C:14]1C=CC=C[CH:15]=1.[CH:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>O>[C:10]([C:7]1[CH:6]=[CH:5][C:4]([N:13]=[C:14]([CH3:15])[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:9][CH:8]=1)(=[O:12])[CH3:11]
Reactant: Nc1ccccc1
Reactant: c1ccccc1
Reactant: CC(=O)c1ccc(C(C)=O)cc1
Solvent: O
Product: CC(=O)c1ccc(N=C(C)c2ccccc2)cc1

Procedure:
A solution of p-diacetylbenzene (50 g), aniline (80 g) and benzene (120 ml) was refluxed in the presence of molecular sieve (10 g) with continuous removal of water. The crude product was crystallized from ethanol to give p-acetyl-N-(α-methyl benzylidene) aniline (XXIII). XXIII had a melting point of 205° C.
Reaction SMILES: [CH3:1][C:2]([S@:5]([NH2:7])=[O:6])([CH3:4])[CH3:3].[CH2:8]1[CH:10]([CH:11](O)C#N)[CH2:9]1>C1COCC1.[Cl-].[Na+].O>[CH:10]1(/[CH:11]=[N:7]/[S@@:5]([C:2]([CH3:4])([CH3:3])[CH3:1])=[O:6])[CH2:8][CH2:9]1
Reactant: CC(C)(C)[S@](N)=O
Reactant: N#CC(O)C1CC1
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)[S@@](=O)/N=C/C1CC1
Yield: 102.8 %

Procedure:
(R)-2-Methylpropane-2-sulfinamide (25) (8.63 g, 71.3 mmol) and Ti(OEt)4 (30 mL, 142.6 mmol) were added to a solution of cyclopropylcarboxaldehyde (24) (5 g, 71.3 mmol) in THF (142 mL). The reaction mixture was stirred at rt for 17 h after which brine (142 mL) was added and the resulting suspension was filtered through a pad of Celite. The filtrate was extracted with EtOAc (200 mL) and the organic phase was dried (Na2SO4), filtered and concentrated under vacuum to give 12.7 g (quant) of (R,E)-N-(cyclopropylmethylene)-2-methylpropane-2-sulfinamide (26). Retention time (min)=1.459 method [1], MS (m/z) 174.1 (M+H)+.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH:14]2[CH2:17][N:16]([C:18]([C:20]3[CH:21]=[C:22]4[C:27](=[CH:28][CH:29]=3)[CH2:26][NH:25][CH2:24][CH2:23]4)=[O:19])[CH2:15]2)[CH2:10][CH2:9]1)=[O:7].[CH:30](=O)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>C(Cl)Cl.O>[CH2:30]([N:25]1[CH2:24][CH2:23][C:22]2[C:27](=[CH:28][CH:29]=[C:20]([C:18]([N:16]3[CH2:17][CH:14]([N:11]4[CH2:12][CH2:13][N:8]([C:6]([C:2]5[S:1][CH:5]=[CH:4][N:3]=5)=[O:7])[CH2:9][CH2:10]4)[CH2:15]3)=[O:19])[CH:21]=2)[CH2:26]1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: O=Cc1ccccc1
Reactant: O=C(c1ccc2c(c1)CCNC2)N1CC(N2CCN(C(=O)c3nccs3)CC2)C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: O=C(c1ccc2c(c1)CCN(Cc1ccccc1)C2)N1CC(N2CCN(C(=O)c3nccs3)CC2)C1
Reaction time: 8 h
Yield: 63.6 %

Procedure:
A solution of Cpd 916 (50 mg, 0.121 mmol) and benzaldehyde 23a (0.014 mL, 0.134 mmol) in CH2Cl2 (2 mL) was stirred at room temperature for 30 min. Sodium triacetoxyborohydride (38.6 mg, 0.182 mmol) was added and the mixture was stirred overnight. The resulting mixture was combined with CH2Cl2 and H2O, and pH of the water layer was adjusted to pH˜8 with 1N aqueous NaOH. The organic solution was dried over Na2SO4 and concentrated. Purification the residue by flash column chromatography (silica gel, 2% MeOH/EtOAc) gave Cpd 680 (38.6 mg). 1H NMR (400 MHz, CDCl3): δ 7.89 (d, J=3.2 Hz, 1H), 7.55 (d, J=3.2 Hz, 1H), 7.32-7.44 (m, 6H), 7.3 (d, J=8.1 Hz, 1H), 7.02 (d, J=8.1 Hz, 1H), 4.33-4.63 (m, 2H), 3.99-4.34 (m, 4H), 3.75-3.98 (m, 2H), 3.70 (s, 2H), 3.65 (s, 2H), 3.16-3.30 (m, 1H), 2.93 (t, J=5.7 Hz, 2H), 2.76 (t, J=5.7 Hz, 2H), 2.37-2.60 (m, 4H). MS m/z (M+H+) 502.0.
Reaction SMILES: [CH3:1][N:2]([C:11]1[C:15]2[NH:16][C:17]([C:19]3[S:20][C:21]4([CH2:28][CH2:27][NH:26][CH2:25][CH2:24]4)[CH2:22][N:23]=3)=[CH:18][C:14]=2[S:13][C:12]=1[CH3:29])[S:3]([C:6]1[S:7][CH:8]=[CH:9][CH:10]=1)(=[O:5])=[O:4].C(N(CC)CC)C.[C:37](Cl)(=[O:39])[CH3:38]>O1CCCC1>[C:37]([N:26]1[CH2:27][CH2:28][C:21]2([S:20][C:19]([C:17]3[NH:16][C:15]4[C:11]([N:2]([CH3:1])[S:3]([C:6]5[S:7][CH:8]=[CH:9][CH:10]=5)(=[O:5])=[O:4])=[C:12]([CH3:29])[S:13][C:14]=4[CH:18]=3)=[N:23][CH2:22]2)[CH2:24][CH2:25]1)(=[O:39])[CH3:38]
Reactant: CC(=O)Cl
Reactant: Cc1sc2cc(C3=NCC4(CCNCC4)S3)[nH]c2c1N(C)S(=O)(=O)c1cccs1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=O)N1CCC2(CC1)CN=C(c1cc3sc(C)c(N(C)S(=O)(=O)c4cccs4)c3[nH]1)S2
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 57 %

Procedure:
To a mixture of N-methyl-N-[2-methyl-5-(1-thia-3,8-diazaspiro[4.5]deca-2-en-2-yl)-4H-thieno[3,2-b]pyrrol-3-yl]thiophene-2-sulfonamide (180 mg), triethylamine (78 μL) and tetrahydrofuran (5 mL) was added acetyl chloride (32 μL), and the mixture was stirred at room temperature for 10 min. The reaction mixture was concentrated, 1N hydrochloric acid was added, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography to give N-[5-(8-acetyl-1-thia-3,8-diazaspiro[4.5]deca-2-en-2-yl)-2-methyl-4H-thieno[3,2-b]pyrrol-3-yl]-N-methylthiophene-2-sulfonamide (115 mg, yield 57%) as colorless crystals from a fraction eluted with ethyl acetate-hexane (1:1, volume ratio). melting point 231° C.
Reaction SMILES: C(OC([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([CH2:15][C:16]2[C:24]3[O:23][CH:22]=[CH:21][C:20]=3[CH:19]=[C:18]([NH2:25])[CH:17]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[Cl:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[S:33](Cl)(=[O:35])=[O:34]>>[ClH:26].[ClH:26].[Cl:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[S:33]([NH:25][C:18]1[CH:17]=[C:16]([CH2:15][N:11]2[CH2:12][CH2:13][CH2:14][NH:8][CH2:9][CH2:10]2)[C:24]2[O:23][CH:22]=[CH:21][C:20]=2[CH:19]=1)(=[O:35])=[O:34]
Reactant: O=S(=O)(Cl)c1ccccc1Cl
Reactant: CC(C)(C)OC(=O)N1CCCN(Cc2cc(N)cc3ccoc23)CC1
Product: Cl
Product: O=S(=O)(Nc1cc(CN2CCCNCC2)c2occc2c1)c1ccccc1Cl
Yield: 60.9 %

Procedure:
The title compound was prepared according to the procedure of Example 106, Step 3, starting from 4-(5-amino-benzofuran-7-ylmethyl)-1,4-diazepane-1-carboxylic acid tert-butyl ester (36 mg, 0.10 mmol; obtained in Step 2) and 2-chlorobenzenesulfonyl chloride (21 μL, 0.16 mmol). The crude material was purified with preparative HPLC (System B; 10-40% MeCN). The title compound (16 mg, 33%) was obtained as a colorless solid. HPLC 95%, RT=1.31 min (System A; 10-97% MeCN over 3 min), 96%, RT=1.17 min (System B; 10-97% MeCN over 3 min). 1H NMR (400 MHz, methanol-d4) δ ppm 2.25-2.37 (m, 2H) 3.41-3.48 (m, 2H) 3.48-3.59 (m, J=4.52 Hz, 2H) 3.69-3.75 (m, J=3.51 Hz, 2H) 3.74-3.83 (m, 2H) 4.70 (s, 2H) 6.86 (d, J=2.26 Hz, 1H) 7.36-7.41 (m, 1H) 7.42 (d, J=2.01 Hz, 1H) 7.51-7.59 (m, 3H) 7.85 (d, J=2.01 Hz, 1H) 8.00-8.04 (m, J=7.91, 1.13 Hz, 1H). MS (ESI+) for C20H22ClN3O3S m/z 420 (M+H)+.
Reaction SMILES: [CH2:1]([N:5]1[C:9]2=[C:10](Cl)[N:11]=[N:12][CH:13]=[C:8]2[C:7]([CH3:15])=[C:6]1[CH3:16])[CH:2]=[CH:3][CH3:4].[F:17][C:18]1[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[C:19]=1[CH2:20][OH:21]>>[CH2:1]([N:5]1[C:9]2=[C:10]([O:21][CH2:20][C:19]3[C:18]([F:17])=[CH:25][CH:24]=[CH:23][C:22]=3[F:26])[N:11]=[N:12][CH:13]=[C:8]2[C:7]([CH3:15])=[C:6]1[CH3:16])[CH:2]=[CH:3][CH3:4]
Reactant: CC=CCn1c(C)c(C)c2cnnc(Cl)c21
Reactant: OCc1c(F)cccc1F
Product: CC=CCn1c(C)c(C)c2cnnc(OCc3c(F)cccc3F)c21
Yield: 58.3 %

Procedure:
The title compound (cis/trans=22/78) was prepared as a white powder in 58.3% yield in a similar procedure to that described in Example 1 by using 1-(2-butenyl)-7-chloro-2,3-dimethylpyrrolo[2,3-d]pyridazine (cis/trans=24/76) and 2,6-difluorobenzyl alcohol.
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH:14]([CH2:17][CH2:18][CH2:19][CH3:20])[C:15]#[N:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:21][CH2:22]Br.CS(C)=O.[OH-].[Na+]>O>[C:15]([C:14]([C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[O:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)([CH2:17][CH2:18][CH2:19][CH3:20])[CH2:22][Br:21])#[N:16]
Reactant: BrCBr
Reactant: CCCCC(C#N)c1ccccc1Oc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: CCCCC(C#N)(CBr)c1ccccc1Oc1ccccc1
Yield: 82.3 %

Procedure:
Into a three-necked 300 ml round bottom flask are charged 10 g (0.038 mole) of 2-(2-phenoxyphenyl) hexanenitrile, 6.6 g (0.038 mole) of dibromomethane and 50 ml of dimethyl sulfoxide. To this mixture with stirring is added 3.2 g (0.04 mole) of 50% sodium hydroxide solution dropwise. Reaction mixture is heated to give 60° for two hours and then poured into water and extracted with hexane. Combined hexane extracts are washed with water and dried over MgSO4. Solvent is evaporated under vacuum to give 11.2 g of product.
Reaction SMILES: Br[CH2:2][C:3]1[C:7]2[CH:8]=[C:9]([Cl:12])[CH:10]=[CH:11][C:6]=2[O:5][C:4]=1[C:13]([O:15][CH2:16][CH3:17])=[O:14].[CH3:18][O:19][CH:20]([O:24][CH3:25])[CH2:21][NH:22][CH3:23].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Cl:12][C:9]1[CH:10]=[CH:11][C:6]2[O:5][C:4]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:3]([CH2:2][N:22]([CH2:21][CH:20]([O:24][CH3:25])[O:19][CH3:18])[CH3:23])[C:7]=2[CH:8]=1
Reactant: CCOC(=O)c1oc2ccc(Cl)cc2c1CBr
Reactant: CNCC(OC)OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)c1oc2ccc(Cl)cc2c1CN(C)CC(OC)OC
Reaction time: 30 h

Procedure:
A mixture of ethyl 3-bromomethyl-5-chloro-2-benzofurancarboxylate (52.75 g, 0.166 mol), methylaminoacetaldehyde dimethyl acetal (19.0 g, 0.167 mol) and potassium carbonate (45 g) in dry acetone (600 ml) was stirred under argon for 30 hours, filtered and the filtrate evaporated. The residue was partitioned between ethyl ether and water and the organic phase was dried with magnesium sulfate, filtered, and concentrated to give ethyl 5-chloro-3-[N-(2,2 dimethoxyethyl)-N methyl(aminomethyl)]-2 -benzofurancarboxylate: mp 58°-60° C.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10](Cl)(=[O:12])=[O:11])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].C(N(CC)CC)C.[NH2:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=1>C1COCC1.O>[C:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=2)(=[O:12])=[O:11])=[CH:6][CH:5]=1)(=[O:3])[CH3:2]
Reactant: NCc1ccccn1
Reactant: CC(=O)c1ccc(S(=O)(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)c1ccc(S(=O)(=O)NCc2ccccn2)cc1
Reaction time: 0.08 h
Yield: 52.7 %

Procedure:
Ex-53A: A solution of 4-acetyl-benzenesulfonyl chloride (1.94 g, 8.89 mmol) and triethylamine (1.85 mL, 13.3 mmol) in anhydrous THF (15 mL) was treated with 2-(aminomethyl)pyridine (1.01 g, 9.34 mmol) at room temperature under nitrogen. The reaction mixture was stirred for 5 minutes and a precipitate formed. The reaction mixture was diluted with water (10 mL) and suction filtration gave 4-acetyl-N-pyridin-2-ylmethylbenzenesulfonamide as a yellow solid (1.36 g, 65%). 1H-NMR (300 MHz, DMSO-d6) 8.38 (m, 3H), 8.06 (d, 2H, J=9.0 Hz), 7.87 (d, 2H, J=7.8 Hz), 7.58 (d, 1H, J=8.7 Hz), 7.25 (dd, 1H, J=5.4, 4.5 Hz), 4.04 (d, 2H, J=3.9 Hz), 2.60 (s, 3H).